Immunological niche to analyze progression and heterogeneity of allergic disease

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

Food allergies affect approximately 11% of US adults and 8% of US children. The current standard of care is largely food avoidance. However, accidental exposures can lead to life-threatening allergic reactions, which have financial and quality of life burdens. Measurement of allergen specific IgE levels are the major means by which risk of allergic reaction is assessed, yet IgE levels do not predict response. Furthermore, individuals with an initially mild response may progress to develop severe responses. The immunological differences between mild and severe reactions, or the transitions associated with progression are unknown, yet are critical to identifying the patient population that is most at-risk and the development of therapies that can prevent the development of life-threatening reactions. We have devised a novel technology – a scaffold that serves as a synthetic immunological niche (IN), which captures the systemic immunological changes during disease progression in models of cancer and autoimmune disease. We propose to employ the scaffolds to monitor immune responses to distinguish the heterogeneity of allergic responses, and subsequently for monitoring the responses following therapeutic treatment with an allergen-specific immunotherapy: allergen- encapsulating nanoparticles (NPs). The scaffold allows for longitudinal analysis of immune dynamics within tissues that are distinct from those in blood, and analysis can monitor disease progression and inform the use of targeted therapies such as NPs. The proposed studies are developed in two Aims. Aim 1 will develop a prognostic signature of systemic immune dynamics for IgE/Th2-mediated food allergies. IgE levels indicate the potential for an allergic response but cannot differentiate between sensitized individuals who are tolerant or allergic. We investigate scaffolds as an IN to monitor and predict immune and physiological changes during OFC in allergen-sensitized mice. These dynamic analyses can identify the biological differences underlying severe and mild allergic reactions. Biopsied scaffolds will be characterized by flow cytometry for immune cell types and by gene expression using bulk RNA and single-cell sequencing. A gene expression signature predicting severity of allergic reactions will be developed and validated. Finally, the scaffold analyses will be compared with that from the intestines, demonstrating that the IN recaptiulates the GI environment. Aim 2 will investigate the use of IN to monitor response to NP immunotherapy. NP immunotherapy has been able to attenuate responses in sensitized mice. The scaffold will be analyzed for a signature associated with this either mild or no allergen reactivity. This signature will be used to predict efficacy and identify the therapeutic mechanisms of the NPs, and thus, elucidating the biology associated with a partial or complete response to immunotherapy. Our platform overcomes this critical barrier of predicting severity of allergen reactivity by analyzing immune processes within synthetic tissues, which are reflective of the sensitized organs and can be analyzed for disease biology or identify therapeutic mechanisms of action.